SNPMiner Trials by Shray Alag


SNPMiner Trials: Clinical Trial Report


Report for Clinical Trial NCT03417830

Developed by Shray Alag, 2019.
SNP Clinical Trial Gene

An Adaptive, Open-Label Study to Evaluate the Biodistribution of 89Zirconium-labelled GSK2398852 in the Heart and Other Organs of Patients With Transthyretin Cardiomyopathy (ATTR-CM) Using Positron Emission Tomography (PET) Imaging

The principal aim of this study is to investigate the cardiac uptake of 89Zr-GSK2398852 in subjects with transthyretin cardiomyopathy amyloidosis (ATTR-CM), and its biodistribution to other organs. Low doses of GSK2398852 will be co-administered at levels not high enough for therapeutic benefit. This study will be conducted in two parts: Part A and Part B. Subjects in Part A will participate in up to two dosing sessions and subjects in Part B will participate in one dosing session. Subjects will undergo up to 3 PET scans at varying intervals after 89Zr-GSK2398852 administration. The total duration of study will be approximately 3 to 4 months for subjects in Part A and approximately 2 months for subjects in Part B. Part B of the study will be triggered based on data obtained in Part A and other emerging data.

NCT03417830 Amyloidosis
MeSH: Cardiomyopathies Amyloidosis
HPO: Amyloidosis Cardiomyopathy

3 Interventions

Name: GSK2315698 (CPHPC)

Description: GSK2315698 will be administered as 20 milligrams per hour (20 mg/hour) IV infusion (in the vein) for up to 72 hours followed by 60 milligrams (mg) three times daily as SC injection for 8 days. Dose level and frequency will be adjusted according to renal function.

Type: Drug

Subjects with ATTR-CM in Part A Subjects with ATTR-CM in Part B

Name: GSK2398852 (unlabeled anti-SAP mAb)

Description: Subjects will be administered up to 490 mg of GSK2398852, IV. Dose level will be adjusted based on emerging imaging data.

Type: Drug

Subjects with ATTR-CM in Part A Subjects with ATTR-CM in Part B

Name: 89Zr-GSK2398852 (89Zr-labeled anti-SAP mAb)

Description: 89Zr-GSK2398852 will be available as solution containing 10 mg 89Zr-GSK2398852 for Infusion. Subjects will be administered 37 (Megabecquerel) MBq radioactive dose of 89Zr-GSK2398852 by the IV route at each dosing session.

Type: Drug

Subjects with ATTR-CM in Part A Subjects with ATTR-CM in Part B


Primary Outcomes

Description: PET images will be visually reviewed to assess the radioactivity distribution. SUV is the measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight.

Measure: Standardized Uptake Values (SUV) in focal anatomical regions of the heart following 80-200 milligrams (mg) dose of anti-SAP mAb

Time: Up to Day 6

Description: PET images will be visually reviewed to assess the radioactivity distribution. SUV is the measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight.

Measure: SUV in focal anatomical regions of the heart following an anti-SAP mAb dose between 200 mg and <=500 mg

Time: Up to Day 6

Description: PET images will be visually reviewed to assess the radioactivity distribution. SUV is the measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight.

Measure: SUV of whole heart following 80-200 mg dose of anti-SAP mAb

Time: Up to Day 6

Description: PET images will be visually reviewed to assess the radioactivity distribution. SUV is the measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight.

Measure: SUV of whole heart following an anti-SAP mAb dose between 200 mg and <=500 mg

Time: Up to Day 6

Secondary Outcomes

Description: PET images will be visually reviewed to assess the radioactivity distribution. SUV is the measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight. Focal radioactivity uptake in different tissues will be evaluated.

Measure: Focal radioactivity uptake after 80-200 mg dose of anti-SAP mAb

Time: Up to Day 6

Description: PET images will be visually reviewed to assess the radioactivity distribution. SUV is the measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight. Focal radioactivity uptake in different tissues will be evaluated.

Measure: Focal radioactivity uptake after an anti-SAP mAb dose between 200 mg and <=500 mg

Time: Up to Day 6

Description: PET images will be visually reviewed to assess the radioactivity distribution. SUV is the measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight. Total radioactivity uptake in different tissues will be evaluated.

Measure: Total radioactivity uptake after 80-200 mg dose of anti-SAP mAb

Time: Up to Day 6

Description: PET images will be visually reviewed to assess the radioactivity distribution. SUV is the measured radioactivity concentration corrected for radioactive decay and normalized for administered amount of radioactivity per body weight. Total radioactivity uptake in different tissues will be evaluated.

Measure: Total radioactivity uptake after an anti-SAP mAb dose between 200 mg and <=500 mg

Time: Up to Day 6

Description: Blood samples will be collected at indicated time points for measurement of plasma concentrations of GSK2398852. Plasma concentrations of GSK2398852, will be the total of both 89Zr-labeled and unlabeled mAb.

Measure: Maximum concentration in plasma (Cmax) of total mAb

Time: Day 3 (pre-dose, 4 hours, 7 hours post-dose), Day 4, Day 5, Day 6 and Day 7 post-dose

Description: Blood samples will be collected at indicated time points for measurement of plasma concentrations of GSK2398852. Plasma concentrations of GSK2398852, will be the total of both 89Zr-labeled and unlabeled mAb.

Measure: Time associated with Cmax (Tmax) of total mAb

Time: Day 3 (pre-dose, 4 hours, 7 hours post-dose), Day 4, Day 5, Day 6 and Day 7 post-dose

Description: Blood samples will be collected at indicated time points for measurement of plasma concentrations of GSK2398852. Plasma concentrations of GSK2398852, will be the total of both 89Zr-labeled and unlabeled mAb.

Measure: Clearance of total mAb

Time: Day 3 (pre-dose, 4 hours, 7 hours post-dose), Day 4, Day 5, Day 6 and Day 7 post-dose

Description: Blood samples will be collected at indicated time points for measurement of plasma concentrations of GSK2398852. Plasma concentrations of GSK2398852, will be the total of both 89Zr-labeled and unlabeled mAb.

Measure: Terminal half-life (T1/2) of total mAb

Time: Day 3 (pre-dose, 4 hours, 7 hours post-dose), Day 4, Day 5, Day 6 and Day 7 post-dose

Description: Blood samples will be collected at indicated time points for measurement of plasma concentrations of GSK2398852. Plasma concentrations of GSK2398852, will be the total of both 89Zr-labeled and unlabeled mAb.

Measure: Area under the concentration-time profile (AUC) of total mAb

Time: Day 3 (pre-dose, 4 hours, 7 hours post-dose), Day 4, Day 5, Day 6 and Day 7 post-dose

Description: Blood samples will be collected at indicated time points for measurement of radioactivity. The radioactivity will reflect the total concentration of 89Zr-GSK2398852 and its radioactive metabolites. Plasma radioactive concentration will be measured by scintillation counter.

Measure: Cmax of 89Zr- GSK2398852 pharmacokinetics of radioactivity (radio-PK)

Time: Day 3 (10 minutes, 60 minutes, 4 hours, 7 hours post-dose), Day 4, Day 5 and Day 6 post-dose

Description: Blood samples will be collected at indicated time points for measurement of radioactivity. The radioactivity will reflect the total concentration of 89Zr-GSK2398852 and its radioactive metabolites. Plasma radioactive concentration will be measured by scintillation counter.

Measure: Tmax of 89Zr- GSK2398852 radio-PK

Time: Day 3 (10 minutes, 60 minutes, 4 hours, 7 hours post-dose), Day 4, Day 5 and Day 6 post-dose

Description: Blood samples will be collected at indicated time points for measurement of radioactivity. The radioactivity will reflect the total concentration of 89Zr-GSK2398852 and its radioactive metabolites. Plasma radioactive concentration will be measured by scintillation counter.

Measure: T1/2 of 89Zr- GSK2398852 radio-PK

Time: Day 3 (10 minutes, 60 minutes, 4 hours, 7 hours post-dose), Day 4, Day 5 and Day 6 post-dose

Description: Blood samples will be collected at indicated time points for measurement of radioactivity. The radioactivity will reflect the total concentration of 89Zr-GSK2398852 and its radioactive metabolites. Plasma radioactive concentration will be measured by scintillation counter.

Measure: AUC of 89Zr- GSK2398852 radio-PK

Time: Day 3 (10 minutes, 60 minutes, 4 hours, 7 hours post-dose), Day 4, Day 5 and Day 6 post-dose

Description: An AE is any untoward medical occurrence in a clinical study subject, temporally associated with the use of a study treatment, whether or not considered related to the study treatment. An SAE is defined as any untoward medical occurrence that, at any dose: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent disability/incapacity; is a congenital anomaly/birth defect; other important medical events which may require medical or surgical intervention.

Measure: Number of subjects with adverse events (AEs) and serious adverse events (SAEs)

Time: Up to Day 28

Description: Rash will be graded as Grade 1 to Grade 4 based on symptoms and body surface area affected.

Measure: Number of subjects with skin rashes

Time: Up to Day 28

Description: Cardiovascular adverse events will include myocardial infarction/unstable angina, congestive heart failure, arrhythmias, valvulopathy, pulmonary hypertension, cerebrovascular events/stroke and transient ischemic attack, peripheral arterial thromboembolism, deep venous thrombosis/pulmonary embolism and revascularization.

Measure: Number of subjects with cardiac adverse events

Time: Up to Day 28

Description: Number of subjects with infusion related reactions will be summarized.

Measure: Number of subjects with infusion related reactions

Time: Up to Day 28

Description: The following hematology parameters will be assessed: platelet count, red blood cell (RBC) count, hemoglobin, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), percentage of reticulocytes, neutrophils, lymphocytes, monocytes, eosinophils and basophils.

Measure: Number of subjects with abnormal hematology parameters

Time: Up to Day 28

Description: The following clinical chemistry parameters will be evaluated: blood urea nitrogen (BUN), creatinine, glucose (non-fasting), potassium, sodium, calcium, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, total and direct bilirubin, total protein and albumin.

Measure: Number of subjects with abnormal clinical chemistry parameters

Time: Up to Day 28

Description: The following parameters will be evaluated: specific gravity, potential hydrogen (pH), glucose, protein, blood and ketones by dipstick method. Urine microscopy will be performed if indicated.

Measure: Number of subjects with abnormal urine parameters

Time: Up to Day 28

Description: The following cardiac chemistry parameters will be evaluated: troponin T and N-terminal prohormone of brain natriuretic peptide (NT-ProBNP).

Measure: Number of subjects with cardiac safety parameters of clinical significance

Time: Up to Day 28

Description: 12-lead ECGs will be obtained in a semi-supine position using an automated ECG machine after approximately 5 minutes of rest for the subject.

Measure: Number of subjects with abnormal electrocardiogram (ECG)

Time: Up to Day 28

Description: Inpatient cardiac monitoring will be performed using inpatient lead II cardiac telemetry.

Measure: Number of subjects with abnormal inpatient cardiac telemetry

Time: Up to Day 11

Description: Outpatient cardiac monitoring will be performed using a non-implantable remote cardiac telemetry device.

Measure: Number of subjects with abnormal outpatient cardiac telemetry

Time: Up to Day 18

Description: Temperature will be measured in a semi-supine position after 5 minutes of rest.

Measure: Number of subjects with abnormal temperature

Time: Up to Day 28

Description: Systolic and diastolic blood pressure will be measured in a semi-supine position after 5 minutes of rest.

Measure: Number of subjects with abnormal blood pressure

Time: Up to Day 28

Description: Pulse rate will be measured in a semi-supine position after 5 minutes of rest.

Measure: Number of subjects with abnormal pulse rate

Time: Up to Day 28

Description: Respiratory rate will be measured in a semi-supine position after 5 minutes of rest.

Measure: Number of subjects with abnormal respiratory rate

Time: Up to Day 28

Description: A brief physical examination will be performed, including assessments of the skin, lungs, cardiovascular system and abdomen (liver and spleen).

Measure: Number of subjects with abnormal physical examination findings

Time: Up to Day 11

Purpose: Diagnostic

Allocation: Non-Randomized

Sequential Assignment


There is one SNP

SNPs


1 V30M

b) Hereditary ATTR amyloidosis (example, TTR Val30Met) should have a known amyloidogenic TTR mutation demonstrated by genotyping and is recognized to be primarily associated with cardiomyopathy and one of the following: i) Definite histochemical identification of amyloid by Congo red staining and green birefringence in crossed polarized light in cardiac or other tissue biopsy and identification of TTR as the amyloid fibril protein either by immunohistochemistry or proteomic analysis. --- Val30Met ---



HPO Nodes


HPO:
Amyloidosis
Genes 22
SLC7A7 PSEN2 FGA ITM2B LYZ TTR NLRP1 POLA1 APOA1 SAA1 MEFV PRNP NLRP3 IL31RA GSN B2M RET APOE OSMR TNFRSF1A APP CST3
Cardiomyopathy
Genes 431
TPM1 TPM2 TPM3 CDKN1C TACO1 HFE H19-ICR SDHAF1 TREX1 ERBB3 ERCC2 EYA4 ERCC3 BRIP1 ERCC4 ACADL HLA-B ACADS PDGFRA ACADVL MICOS13 PDHA1 DNAJC19 ENPP1 SPEG SMC1A ACTA1 MC2R PEX1 ACTC1 PEX6 PEX7 DPM3 PEX10 PEX12 PEX13 PEX14 ANO5 HMGCL KLHL41 ACTN2 CHKB ADAR TTN HNRNPA1 TTPA TTR TRIP4 HNRNPA2B1 ADCY5 WARS2 ELAC2 PGM1 RYR1 RYR2 RNU4ATAC FANCA FANCC FANCD2 FANCE SLC25A3 SLC2A10 FAH FANCB FANCF FANCG PHYH AARS2 FKTN CLN3 AGL RAB3GAP2 RNASEH2C HPS1 SCN5A MIPEP MIB1 COA5 AHCY GPC4 PEX16 HRAS SCO1 GTF2H5 PKP2 MMP1 MAD2L2 MTO1 FTO PRKAG2 FHL1 FHL2 POMK GMPPB PLN LTBP4 SLC30A10 D2HGDH SDHA SDHB VCL VCP SDHD PMM2 HJV POMT2 TMEM126A NDUFB11 COL7A1 FLNC FOXRED1 MYOT NDUFAF5 ANK1 NEBL TAPT1 SLC25A4 CLIP2 CISD2 RNASEH2A FKRP SGCA WFS1 SGCB SGCD ACAD9 SGSH FOS RRM2B POLG GNPTAB PEX3 NDUFAF3 BAG3 AGPAT2 COX6B1 DOLK SLC19A2 KCNAB2 COX7B COX8A COX10 POMGNT1 COX15 TWNK XK SAMHD1 FASTKD2 TMEM43 GATA5 POMT1 IDH2 TXNRD2 FXN PPARG XRCC2 CPT1A XRCC4 CPT2 FANCM GTF2IRD1 IDUA SKI TCAP SLC40A1 COA8 ABCC6 RBM20 PEX26 RBCK1 NDUFA11 SLC4A1 EPG5 PPP1CB MTFMT LIMS2 CRYAB NBAS LIPT1 VAC14 PIGT NDUFAF4 IGF2 ACAD8 ARSB ATP6 COX1 COX2 UBE2T COX3 KLF1 NEK8 FLAD1 ANKRD1 ND1 ND2 SLC22A5 ND3 ND4 NAXD MRPS14 PPA2 ND5 ND6 ANKRD11 MPLKIP GATAD1 AGK KBTBD13 TRNE TRNF NDUFAF6 CAVIN1 TRNH TRNK TRNL1 HAMP RERE TRNN TRNQ TRNS1 TRNS2 RNASEH1 TRNT TRNV TRNW SUFU MAP2K1 MAP2K2 PRDM16 NEXN SLX4 MMUT H19 MGME1 ATPAF2 SOS1 MYBPC3 ATP5F1D ATP5F1E GABRD COX20 UBR1 IL12B ATP6V1A MYH6 MYH7 ANKS6 NDUFS7 MYL2 MYL3 DCAF8 PSEN1 PSEN2 PET100 SPTA1 SPTB TMEM126B MRPL44 RNF113A VPS33A NAGA NAGLU MAP3K20 GATA4 MYOZ2 BBS2 GBE1 CDH23 NDUFA2 NDUFA4 PEX11B GPR101 ITGA7 NEB NDUFA9 NDUFA10 COQ2 BCS1L NDUFB8 NDUFS1 NDUFS2 MRPS22 NDUFS3 STAR NDUFV1 NDUFS4 ITPA NDUFS8 NDUFV2 FBXL4 IFIH1 DES GJA5 JUP COA6 PTPN11 NEU1 NF1 GLA GPC3 NDUFA12 BRCA1 GLB1 ALMS1 BRAF BRCA2 CLPB FIG4 KCNH1 SURF1 KCNJ8 MYPN TMEM70 SYNE2 VPS13A PEX19 C1QBP PEX2 PEX5 KCNQ1 DLD DMD SARDH MYO18B RMND1 GTPBP3 KCNQ1OT1 GNS ALG1 TAZ RAD51 RAD51C RNASEH2B KRAS RAF1 LIAS SCO2 NPPA PNPLA2 SLC25A20 NRAS DSC2 MLX NUP107 GNE DSG2 NDUFAF2 DSP COG7 DTNA SYNE1 TAF1A HGSNAT SLC19A3 LAMA2 LAMA3 LAMA4 JPH2 BAZ1B LAMB3 ABCC9 LAMC2 LAMP2 FANCL AIP CAV1 RFC2 ECHS1 PPCS SHOC2 SELENON BOLA3 OPA1 CSRP3 PALB2 TSFM GSN RFWD3 MLYCD YARS2 TFR2 RIT1 TGFB1 TGFB3 NDUFA13 RMRP USP8 TNNI3K LIMK1 GTF2E2 LDB3 TRNT1 GTF2I ABHD5 NDUFAF1 LMNA ATAD3A TK2 COQ4 GUSB FANCI GYG1 GYS1 MRAP TMPO BSCL2 HSD17B10 ELN HADHA MRPL3 HADHB HADH EMD TANGO2 TNNC1 POLG2 TNNI3 KAT6B HBB TNNT2 PCCA PCCB NNT HCCS HACD1 TBL2 TOP3A EPB42 COX14 TPI1